During early development many neurons form synapses exuberantly, which are later refined during precise time windows often referred to as critical periods. Dynamic synapse formation and elimination occurs during these critical periods in an activity-dependent manner. The DD GABAergic motor neurons provide a model to study a developmentally programmed form of synaptic remodeling (1, 2). The DD neurons are born in the embryo and initially form neuromuscular junctions (NMJs) with ventral body muscles. At the end of the L1, the ventral DD NMJs are eliminated and dorsal NMJs are formed. In contrast, the VD neurons, GABAergic motor neurons born post-embryonically, do not undergo this remodeling process. VD-specific expression of the UNC-55 transcription factor is responsible for inhibiting synapse remodeling, as
unc-55 mutants undergo ectopic VD remodeling. Therefore, among the genes that are regulated by UNC-55, we expect to find some that are required for synapse remodeling. We show that UNC-55 represses expression of the hunchback-like transcription factor HBL-1 in the VD neurons, and that
hbl-1 is required for ectopic VD remodeling in
unc-55 mutants. Moreover, HBL-1 also promotes the normal remodeling of DD synapses, as
hbl-1 mutants exhibit significant delays in the timing of DD synapse remodeling.
hbl-1 is negatively regulated by the
let-7 family of microRNAs: animals lacking these microRNAs express greater levels of
hbl-1 and undergo DD synaptic remodeling precociously. Similarly, mutations that enhance synaptic transmission, and which consequently increase overall neuronal network activity, have increased
hbl-1 expression and precocious DD remodeling. Together, our data suggest that
hbl-1 is an important regulator of the critical period of synapse remodeling. The timing of DD remodeling is controlled by pathways regulating HBL-1 expression. These results may provide a genetic model for how the critical period of a specific form of synaptic remodeling is determined. 1. White, J. G., Albertson, D. G. & Anness, M. A. R. (1976) Nature 271, 764-766. 2. Hallam, S. J. & Jin, Y. (1998) Nature 395, 78-82.